Oxysterols and methods of use thereof

ABSTRACT

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R 1 , R 2 , R 3 , and R 6 , R 11a , and R 11b  are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application under 35U.S.C. § 371 of International Application PCT/US2017/041199, filed Jul.7, 2017, which claims priority to U.S. Ser. No. 62/359,532 filed Jul. 7,2016, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/orNR3 subunits and possess distinct recognition sites for exogenous andendogenous ligands. These recognition sites include binding sites forglycine, and glutamate agonists and modulators. NMDA receptors areexpressed in the peripheral tissues and the CNS, where they are involvedin excitatory synaptic transmission. Activating these receptorscontributes to synaptic plasticity in some circumstances andexcitotoxicity in others. These receptors are ligand-gated ion channelsthat admit Ca2+ after binding of the glutamate and glycine, and arefundamental to excitatory neurotransmission and normal CNS function.Positive modulators may be useful as therapeutic agents with potentialclinical uses as cognitive enhancers and in the treatment of psychiatricdisorders in which glutamatergic transmission is reduced or defective(see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46),10318-10325). In contrast, negative modulators may be useful astherapeutic agents with potential clinical uses in the treatment ofpsychiatric disorders in which glutamatergic transmission ispathologically increased (e.g., treatment resistant depression).

Oxysterols are cholesterol analogs that are modulators of NMDA receptorfunction. There is a need for new oxysterols that modulate the NMDAreceptor for the prevention and treatment of conditions associated withNMDA expression and function. Compounds, compositions, and methodsdescribed herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are new oxysterols useful for preventing and/or treatinga broad range of disorders, including, but not limited to, NMDA-mediateddisorders. Further provided are pharmaceutical compositions comprisingthe compounds of the present invention, and methods of their use andtreatment.

In one aspect, provided herein are compounds according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or C₁-C₆ alkyl; each of R² and R³ is independentlyhydrogen, C₁-C₆ alkyl, or carbocyclyl, or R² and R³, together with thecarbon atom to which they are attached, form a 3-8 membered ring; R⁶ isabsent or hydrogen; R^(11a) is hydrogen or C₁-C₆ alkyl (e.g., methyl)and R^(11b) is —OH, or C₁-C₆ alkyl, or R^(11a) and R^(11b) are joinedtogether to form oxo; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; and when one of the

is a double bond, R⁶ is absent.

In some embodiments, R^(11a) and R^(11b) are not joined together to formoxo.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen, methyl or ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃. Insome embodiments, R¹ is unsubstituted C₁₋₆ alkyl (e.g., —CH₃ or—CH₂CH₃). In some embodiments, R¹ is hydrogen. In some embodiments, R¹is —CH₃. In some embodiments, R¹ is —CH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃. In some embodiments, each of R² and R³ isindependently methyl, isopropyl, or tert-butyl.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl (e.g., tert-butyl), —CF₃, or —CH₂CF₃.

In some embodiments, R^(11a) is hydrogen and R^(11b) is —OH. In someembodiments, R^(11a) is C₁-C₆ alkyl (e.g., methyl) and R^(11b) is —OH.In some embodiments, R^(11a) and R^(11b) are joined together to formoxo.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-A) or Formula (I-B):

or a pharmaceutically acceptable salt thereof.

In some embodiments, each of

is a single bond.

In some embodiments, the compound of Formula (I) is a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-A) or Formula (II-B):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen, methyl, ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, —CF₃, or —CH₂CF₃.

In an aspect, provided herein is a compound selected from the groupconsisting of:

In an aspect, provided herein is a pharmaceutically acceptable salt of acompound selected from the group consisting of:

In some embodiments, the compound of Formula (I) is a compound ofFormula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen. In some embodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ ishydrogen, methyl, ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl (e.g., tert-butyl), —CF₃, or —CH₂CF₃.

In an aspect, provided herein is a pharmaceutical composition comprisinga compound described herein, or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

In an aspect, provided herein is a method of inducing sedation oranesthesia comprising administering to a subject an effective amount ofa compound described herein, or pharmaceutically acceptable saltthereof, or pharmaceutical composition thereof.

In an aspect, provided herein is a method for treating or preventing adisorder described herein, comprising administering to a subject in needthereof an effective amount of a compound described herein, orpharmaceutically acceptable salt thereof, or pharmaceutical compositionthereof.

In some embodiments, the disorder is a gastrointestinal (GI) disordere.g., constipation, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD) (e.g., ulcerative colitis, Crohn's disease), structuraldisorders affecting the GI, anal disorders (e.g., hemorrhoids, internalhemorrhoids, external hemorrhoids, anal fissures, perianal abscesses,anal fistula), colon polyps, cancer, colitis.

In some embodiments, the disorder is inflammatory bowel disease.

In some embodiments, the disorder is cancer, diabetes, or a sterolsynthesis disorder.

In an aspect, provided herein is a method for treating or preventing acondition (e.g., CNS-related condition) comprising administering to asubject in need thereof an effective amount of a compound describedherein, or pharmaceutically acceptable salt thereof, or pharmaceuticalcomposition thereof. In some embodiments, the condition is an adjustmentdisorder, anxiety disorders (including obsessive-compulsive disorder,posttraumatic stress disorder, social phobia, generalized anxietydisorder), cognitive disorders (including Alzheimer's disease and otherforms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disesase dementia, and Lewy body dementia),dissociative disorders, eating disorders, mood disorders (includingdepression (e.g., postpartum depression), bipolar disorder, dysthymicdisorder, suicidality), schizophrenia or other psychotic disorders(including schizoaffective disorder), sleep disorders (includinginsomnia), substance abuse-related disorders, personality disorders(including obsessive-compulsive personality disorder), autism spectrumdisorders (including those involving mutations to the Shank group ofproteins (e.g., Shank3)), neurodevelopmental disorders (including Rettsyndrome), multiple sclerosis, sterol synthesis disorders,Smith-Lemli-Optiz syndrome, pain (including acute pain, chronic pain,and neuropathic pain), seizure disorders (including status epilepticusand monogenic forms of epilepsy such as Dravet's disease, TuberousSclerosis Complex (TSC), and infantile spasms), stroke, subarachnoidhemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic braininjury, movement disorders (including Huntington's disease andParkinson's disease) attention deficit disorder, attention deficithyperactivity disorder, metabolic encephalopathies (includingphenylketoneuria), post-partum psychosis, syndromes associated with hightiters of anti-NMDA receptor antibodies (including anti-NMDA receptorencephalitis), neurodegenerative disorders, neuroinflammation,neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

In some embodiments, the disorder is sterol synthesis disorder.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methodsknown to those skilled in the art, including chiral high pressure liquidchromatography (HPLC), supercritical fluid chromatography (SFC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

The invention additionally encompasses compounds described herein asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

The absolute configuration of an asymmetric center can be determinedusing methods known to one skilled in the art. In some embodiments, theabsolute configuration of an asymmetric center in a compound can beelucidated from the X-ray single-crystal structure of the compound. Insome embodiments, an asymmetric center of known absolute configurationcan be introduced into a compound with a chiral reactant, e.g., a chiralepoxide.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

“Aliphatic” refers to an alkyl, alkenyl, alkynyl, or cycloalkyl group,as defined herein.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁) ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. When a range or numberof carbons is provided for a particular alkylene group, it is understoodthat the range or number refers to the range or number of carbons in thelinear carbon divalent chain. Alkylene groups may be substituted orunsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms andfor 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-cyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and CR⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.

In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstitued alkyl, substituted or unsubstitued alkenyl, substitutedor unsubstitued alkynyl, substituted or unsubstitued carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstitued heteroaryl, as defined herein.“Alkanoyl” is an acyl group wherein R²⁰ is a group other than hydrogen.Representative acyl groups include, but are not limited to, formyl(—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstitued alkenyl, substituted orunsubstitued alkynyl, substituted or unsubstitued carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstitued heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo” refers to the group ═O.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein each R³⁸ is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstitued alkenyl, substituted or unsubstituedalkynyl, substituted or unsubstitued carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstitued heteroaryl, or an amino protecting group,wherein at least one of R³⁸ is not a hydrogen. In certain embodiments,each R³⁸ is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈alkenyl, C₃-C₈ alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substitutedwith halo or hydroxy; C₃-C₅ alkenyl, substituted with halo or hydroxy;C₃-C₅ alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀aryl), —(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀cycloalkyl), or —(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is aninteger between 0 and 8, each of which is substituted by unsubstitutedC₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄haloalkoxy or hydroxy; or both R³⁸ groups are joined to form an alkylenegroup.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance ofdoubt, the term ‘substituted amino’ includes the groups alkylamino,substituted alkylamino, alkylarylamino, substituted alkylarylamino,arylamino, substituted arylamino, dialkylamino, and substituteddialkylamino as defined below. Substituted amino encompasses bothmonosubstituted amino and disubstituted amino groups.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group issubstituted with a cycloalkyl group. Typical cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl groupis substituted with a heterocyclyl group. Typical heterocyclylalkylgroups include, but are not limited to, pyrrolidinylmethyl,piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl,and the like.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆-10 aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl), alkyl), alkyl)⁺X⁻,—NH(C₁₋₆ alkyl)⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl),—OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl), —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),—NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl), —NHC(═O)NH(C₁₋₆ alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, alkyl)₃-C(═S)N(C₁₋₆alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂,—OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminalR^(gg) substituents can be joined to form ═O or ═S; wherein X⁻ is acounterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, O⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂₀R^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention provides oxysterolsuseful for preventing and/or treating a broad range of disorders,including, but not limited to, NMDA-mediated disorders.

Compounds

In one aspect, provided herein are compounds according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or C₁-C₆ alkyl; each of R² and R³ is independentlyhydrogen, C₁-C₆ alkyl, or carbocyclyl, or R² and R³, together with thecarbon atom to which they are attached, form a 3-8 membered ring; R⁶ isabsent or hydrogen; R^(11a) is hydrogen or C₁-C₆ alkyl (e.g., methyl)and R^(11b) is —OH, or C₁-C₆ alkyl, or R^(11a) and R^(11b) are joinedtogether to form oxo; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; and when one of the

is a double bond, R⁶ is absent.

In some embodiments, R^(11a) and R^(11b) are not joined together to formoxo.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen, methyl or ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃. Insome embodiments, R¹ is unsubstituted C₁₋₆ alkyl (e.g., —CH₃ or—CH₂CH₃). In some embodiments, R¹ is hydrogen. In some embodiments, R¹is —CH₃. In some embodiments, R¹ is —CH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃. In some embodiments, each of R² and R³ isindependently methyl, isopropyl, or tert-butyl.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl (e.g., tert-butyl), —CF₃, or —CH₂CF₃.

In some embodiments, R^(11a) is hydrogen and R^(11b) is —OH. In someembodiments, R^(11a) is C₁-C₆ alkyl (e.g., methyl) and R^(11b) is —OH.In some embodiments, R^(11a) and R^(11b) are joined together to formoxo.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-A) or Formula (I-B):

or a pharmaceutically acceptable salt thereof.

In some embodiments, each of

is a single bond.

In some embodiments, the compound of Formula (I) is a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-A) or Formula (II-B):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen, methyl, ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, —CF₃, or —CH₂CF₃.

In an aspect, provided herein is a compound selected from the groupconsisting of:

In an aspect, provided herein is a pharmaceutically acceptable salt of acompound selected from the group consisting of:

In some embodiments, the compound of Formula (I) is a compound ofFormula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ ishydrogen. In some embodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ ishydrogen, methyl, ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃.

In some embodiments, each of R² and R³ is independently hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl (e.g., tert-butyl),—CF₃, or —CH₂CF₃.

In some embodiments, R² is hydrogen, methyl, ethyl, or —CF₃.

In some embodiments, R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl (e.g., tert-butyl), —CF₃, or —CH₂CF₃.

Alternative Embodiments

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions. For example, hydrogen maybe ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example,¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, forexample, ¹⁵N, and the like. In other embodiments, a particular isotope(e.g., ³H, ¹³C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 99%, or at least 99.9% of the totalisotopic abundance of an element that occupies a specific site of thecompound.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound of Formula (I).

When employed as pharmaceuticals, the compounds provided herein aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, thecarrier is a parenteral carrier, oral or topical carrier.

The present invention also relates to a compound of Formula (I) orpharmaceutical composition thereof for use as a pharmaceutical or amedicament.

Generally, the compounds provided herein are administered in atherapeutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The pharmaceutical compositions provided herein can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal administration. Depending onthe intended route of delivery, the compounds provided herein arepreferably formulated as either injectable or oral compositions or assalves, as lotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The above-described components for orally administrable, injectable, ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's The Science and Practice of Pharmacy, 21stedition, 2005, Publisher: Lippincott Williams & Wilkins, which isincorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of Formula (I). In one embodiment, theformulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, theformulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of Formula (I). The acid which may beused to prepare the pharmaceutically acceptable salt is that which formsa non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 240-270 mg tablets(80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2—Capsules

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg ofactive compound per capsule).

Exemplary Formulation 3—Liquid

A compound of Formula (I), or pharmaceutically acceptable salt thereof,(125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) andthe resultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 450-900 mg tablets(150-300 mg of active compound) in a tablet press.

Exemplary Formulation 5—Injection

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Exemplary Formulation 6—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 90-150 mg tablets(30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 30-90 mg tablets (10-30mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 0.3-30 mg tablets(0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 9—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 150-240 mg tablets(50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 10—Tablets

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions the regimenfor treatment usually stretches over many months or years so oral dosingis preferred for patient convenience and tolerance. With oral dosing,one to five and especially two to four and typically three oral dosesper day are representative regimens. Using these dosing patterns, eachdose provides from about 0.01 to about 20 mg/kg of the compound providedherein, with preferred doses each providing from about 0.1 to about 10mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

Methods of Treatment and Use

Compounds of the present invention, e.g., a compound of Formula (I), andpharmaceutically acceptable salts thereof, as described herein, aregenerally designed to modulate NMDA function, and therefore to act asoxysterols for the treatment and prevention of, e.g., CNS-relatedconditions in a subject. In some embodiments, the compounds describedherein, e.g., a compound of Formula (I), and pharmaceutically acceptablesalts thereof, as described herein, are generally designed to penetratethe blood brain barrier (e.g., designed to be transported across theblood brain barrier). Modulation, as used herein, refers to, forexample, the inhibition or potentiation of NMDA receptor function. Incertain embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, acts as a negative allosteric modulator (NAM)of NMDA, and inhibit NMDA receptor function. In certain embodiments, thepresent invention, e.g., a compound of Formula (I), or pharmaceuticallyacceptable salt thereof, acts as a positive allosteric modulator (PAM)of NMDA, and potentiate NMDA receptor function. In ceratin embodiments,the compound of Formula (I), or pharmaceutically acceptable saltthereof, blocks or reduces the potentiation or inhibition of NMDAreceptor function by a naturally-occurring substrate. Such compounds donot act as negative allosteric modulators (NAMs) or positive allostericmodulators (PAMs) of NMDA. In some embodiments, the disorder is cancer.In some embodiments, the disorder is diabetes. In some embodiments, thedisorder is a sterol synthesis disorder. In some embodiments, thedisorder is a gastrointestinal (GI) disorder, e.g., constipation,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g.,ulcerative colitis, Crohn's disease), structural disorders affecting theGI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, or colitis. In some embodiments, the disorder isinflammatory bowel disease.

Exemplary conditions related to NMDA-modulation include, but are notlimited to, gastrointestinal (GI) disorder, e.g., constipation,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g.,ulcerative colitis, Crohn's disease), structural disorders affecting theGI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, colitis, and CNS conditions, e.g., as described herein.

Exemplary conditions (e.g., CNS conditions) related to NMDA-modulationinclude, but are not limited to, adjustment disorders, anxiety disorders(including obsessive-compulsive disorder, posttraumatic stress disorder,social phobia, generalized anxiety disorder), cognitive disorders(including Alzheimer's disease and other forms of dementia includingcortico-basal dementia-progressive supranucelar palsy, frontal-temoraldementia, primary progressive aphasia, Parkinson's disesase dementia,and Lewy body dementia), dissociative disorders, eating disorders, mooddisorders (including depression (e.g., postpartum depression), bipolardisorder, dysthymic disorder, suicidality), schizophrenia or otherpsychotic disorders (including schizoaffective disorder), sleepdisorders (including insomnia), substance abuse-related disorders,personality disorders (including obsessive-compulsive personalitydisorder), autism spectrum disorders (including those involvingmutations to the Shank group of proteins (e.g., Shank3)),neurodevelopmental disorders (including Rett syndrome), multiplesclerosis, sterol synthesis disorders, Smith-Lemli-Optiz syndrome, pain(including acute pain, chronic pain, and neuropathic pain), seizuredisorders (including status epilepticus and monogenic forms of epilepsysuch as Dravet's disease, Tuberous Sclerosis Complex (TSC), andinfantile spasms), stroke, subarachnoid hemorrhage, intracerebralhemorrhage, cerebral ischemia, traumatic brain injury, movementdisorders (including Huntington's disease and Parkinson's disease)attention deficit disorder, attention deficit hyperactivity disorder,metabolic encephalopathies (including phenylketoneuria), post-partumpsychosis, syndromes associated with high titers of anti-NMDA receptorantibodies (including anti-NMDA receptor encephalitis),neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus,Niemann-Pick C disorder, and tinnitus.

In certain embodiments, compounds of the present invention, e.g., acompound of Formula (I), or pharmaceutically acceptable salt thereof,can be used to induce sedation or anesthesia.

In certain embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofadjustment disorders, anxiety disorders (including obsessive-compulsivedisorder, posttraumatic stress disorder, social phobia, generalizedanxiety disorder), cognitive disorders (including Alzheimer's diseaseand other forms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disesase dementia, and Lewy body dementia),dissociative disorders, eating disorders, mood disorders (includingdepression (e.g., postpartum depression), bipolar disorder, dysthymicdisorder, suicidality), schizophrenia or other psychotic disorders(including schizoaffective disorder), sleep disorders (includinginsomnia), substance abuse-related disorders, personality disorders(including obsessive-compulsive personality disorder), autism spectrumdisorders (including those involving mutations to the Shank group ofproteins (e.g., Shank3)), neurodevelopmental disorders (including Rettsyndrome), multiple sclerosis, sterol synthesis disorders,Smith-Lemli-Optiz syndrome, pain (including acute pain, chronic pain,and neuropathic pain), seizure disorders (including status epilepticusand monogenic forms of epilepsy such as Dravet's disease, TuberousSclerosis Complex (TSC), and infantile spasms), stroke, subarachnoidhemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic braininjury, movement disorders (including Huntington's disease andParkinson's disease) attention deficit disorder, attention deficithyperactivity disorder, metabolic encephalopathies (includingphenylketoneuria), post-partum psychosis, syndromes associated with hightiters of anti-NMDA receptor antibodies (including anti-NMDA receptorencephalitis), neurodegenerative disorders, neuroinflammation,neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

In certain embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofadjustment disorders, anxiety disorders (including obsessive-compulsivedisorder, posttraumatic stress disorder, social phobia, generalizedanxiety disorder), cognitive disorders (including Alzheimer's diseaseand other forms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disesase dementia, and Lewy body dementia),substance abuse-related disorders, dissociative disorders, eatingdisorders mood disorders (including depression (e.g., postpartumdepression), bipolar disorder, dysthymic disorder, suicidality),schizophrenia or other psychotic disorders (including schizoaffectivedisorder), personality disorders (including obsessive-compulsivepersonality disorder), autism spectrum disorders (including thoseinvolving mutations to the Shank group of proteins (e.g., Shank3)), orpost-partum psychosis.

In certain embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofneurodevelopmental disorders (including Rett syndrome), multiplesclerosis, sterol synthesis disorders, Smith-Lemli-Optiz syndrome, pain(including acute pain, chronic pain, and neuropathic pain), seizuredisorders (including status epilepticus and monogenic forms of epilepsysuch as Dravet's disease, Tuberous Sclerosis Complex (TSC), andinfantile spasms), stroke, subarachnoid hemorrhage, intracerebralhemorrhage, cerebral ischemia, traumatic brain injury, movementdisorders (including Huntington's disease and Parkinson's disease)attention deficit disorder, attention deficit hyperactivity disorder,metabolic encephalopathies (including phenylketoneuria), syndromesassociated with high titers of anti-NMDA receptor antibodies (includinganti-NMDA receptor encephalitis), neurodegenerative disorders,neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, ortinnitus.

In some embodiments, a compound of the invention, e.g., a compound ofFormula (I) that acts as a PAM of NMDA receptor function can be usefulin the treatment or prevention of conditions (e.g., CNS-relatedconditions) including schizophrenia or other psychotic disorders(including schizoaffective disorder), sleep disorders (includinginsomnia), autism spectrum disorders (including those involvingmutations to the Shank group of proteins (e.g., Shank3)), multiplesclerosis, movement disorders (including Huntington's disease andParkinson's disease), attention deficit disorder, attention deficithyperactivity disorder, metabolic encephalopathies (includingphenylketoneuria), post-partum psychosis, and syndromes associated withhigh titers or anti-NMDA receptor antibodies (including anti-NMDAreceptor encephalitis).

In some embodiments, a compound of the invention, e.g., a compound ofFormula (I), that acts as a NAM of NMDA receptor function can be usefulin the treatment or prevention of conditions (e.g., CNS-relatedconditions) including anxiety disorders (including obsessive-compulsivedisorder, posttraumatic stress disorder, social phobia, generalizedanxiety disorder), mood disorders (including depression (e.g.,postpartum depression), bipolar disorder, dysthymic disorder,suicidality), personality disorders (including obsessive-compulsivepersonality disorder), neurodevelopmental disorders (including Rettsyndrome), pain (including acute and chronic pain), seizure disorders(including status epilepticus and monogenic forms of epilepsy such asDravet's disease, and Tuberous Sclerosis Complex (TSC)), stroke,traumatic brain injury, adjustment disorders, neuropsychiatric lupus,and tinnitus.

In some embodiments, a compound of the invention, e.g., a compound ofFormula (I), that acts as a PAM or a NAM of NMDA receptor function canbe useful in the treatment or prevention of conditions (e.g.,CNS-related conditions) including cognitive disorders (includingAlzheimer's disease and other forms of dementia including cortico-basaldementia-progressive supranucelar palsy, frontal-temoral dementia,primary progressive aphasia, Parkinson's disease dementia, and Lewy bodydementia), sterol synthesis disorders, and eating disorders.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention,e.g., a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In yet another aspect, the present invention provides a combination of acompound of the present invention, e.g., a compound of Formula (I), orpharmaceutically acceptable salt thereof, and another pharmacologicallyactive agent. The compounds provided herein can be administered as thesole active agent or they can be administered in combination with otheragents. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent and alternating administration.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs). Tremor includes hereditary, degenerative, and idiopathicdisorders such as Wilson's disease, Parkinson's disease, and essentialtremor, respectively; metabolic diseases (e.g., thyoid-parathyroid-,liver disease and hypoglycemia); peripheral neuropathies (associatedwith Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complexregional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese,arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium,cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine,steroids, valproate, amiodarone, thyroid hormones, vincristine); andpsychogenic disorders. Clinical tremor can be classified intophysiologic tremor, enhanced physiologic tremor, essential tremorsyndromes (including classical essential tremor, primary orthostatictremor, and task- and position-specific tremor), dystonic tremor,parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubraltremor), palatal tremor, neuropathic tremor, toxic or drug-inducedtremor, and psychogenic tremor. Other forms of tremor include cerebellartremor or intention tremor, dystonic tremor, essential tremor,orthostatic tremor, parkinsonian tremor, physiological tremor,psychogenic tremor, or rubral tremor.

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawl,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptons foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.

Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part.

Tourette Syndrome is an inherited neuropsychiatric disorder with onsetin childhood, characterized by multiple motor tics and at least onevocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormalitiy in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cataonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior.

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during preganancy. This depression isreferred to herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequnces. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or physchological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

Anxiety Disorders

Provided herein are methods for treating anxiety disorders. Anxietydisorder is a blanket term covering several different forms of abnormaland pathological fear and anxiety. Current psychiatric diagnosticcriteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Epilepsy

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

Epileptogenesis is a gradual process by which a normal brain developsepilepsy (a chronic condition in which seizures occur). Epileptogenesisresults from neuronal damage precipitated by the initial insult (e.g.,status epilepticus).

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures;

recurrent seizures; status epilepticus seizures, e.g., refractoryconvulsive status epilepticus, non-convulsive status epilepticusseizures; refractory seizures; myoclonic seizures; tonic seizures;tonic-clonic seizures; simple partial seizures; complex partialseizures; secondarily generalized seizures; atypical absence seizures;absence seizures; atonic seizures; benign Rolandic seizures; febrileseizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative pyrazoles that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

Exemplary general method for preparative HPLC: Column: Waters RBridgeprep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH₄HCO₃)(30 L water, 24 g NH₄HCO₃, 30 mL NH₃.H₂O). Flow rate: 25 mL/min

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 ml/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45° C.

NMDA Modulation

NMDA potentiation in mammalian cells which expressed NMDA receptors wasassessed using the whole cell patch clamp to determine the PAM activityof compounds as described below. An automatic patch-clamp system can beused determine the NAM activity of compounds as described below.

Whole-Cell Patch Clamp of Mammalian Cells (Ionworks Barracuda (IWB))

The whole-cell patch-clamp technique was used to investigate the effectsof positive allosteric modulating activity of test compounds onGlunN1/GluN2A and GluN2B glutamate receptors expressed in mammaliancells. The results are shown in Tables 1 and 2.

HEK293 cells were transformed with adenovirus 5 DNA and transfected withcDNA encoding the human GRIN1/GRIN2A genes. Stable transfectants wereselected using G418 and Zeocin-resistance genes incorporated into theexpression plasmid and selection pressure maintained with G418 andZeocin in the medium. Cells were cultured in Dulbecco's Modified EagleMedium/Nutrient Mixture (D-MEM/F-12) supplemented with 10% fetal bovineserum, 100 μg/ml penicillin G sodium, 100 μg/ml streptomycin sulphate,100 μg/ml Zeocin, 5 μg/ml blasticidin and 500 μg/ml G418.

Test article effects were evaluated in 8-point concentration-responseformat (4 replicate wells/concentration). All test and control solutionscontained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). The testarticle formulations were loaded in a 384-well compound plate using anautomated liquid handling system (SciClone ALH3000, CaliperLifeScienses). The measurements were performed using Ion Works Barracudaplatform following this procedure:

Electrophysiological Procedures:

-   -   a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM        MgCl₂, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.    -   b) Extracellular solution, HB-PS (composition in mM): NaCl, 137;        KCl, 1.0; CaCl₂, 5; HEPES, 10; Glucose, 10; pH adjusted to 7.4        with NaOH (refrigerated until use).    -   c) Holding potential: −70 mV, potential during agonist/PAM        application: −40 mV.        Recording Procedure:    -   a) Extracellular buffer will be loaded into the PPC plate wells        (11 μL per well). Cell suspension will be pipetted into the        wells (9 μL per well) of the PPC planar electrode.    -   b) Whole-cell recording configuration will be established via        patch perforation with membrane currents recorded by on-board        patch clamp amplifiers.    -   c) Two recordings (scans) will be performed. First, during        pre-application of test article alone (duration of        pre-application −5 min) and second, during test articles and        agonist (EC₂₀ L-glutamate and 30 μM glycine) co-application to        detect positive modulatory effects of the test article.

Test Article Administration: The first pre-application will consist ofthe addition of 20 μL of 2× concentrated test article solution and,second, of 20 μL of 1× concentrated test article and agonist at 10 μL/s(2 second total application time).

Potentiating Effect of Positive Allosteric Modulators (PAM) on theChannel

Potentiating effect of positive allosteric modulators (PAM) on thechannel will be calculated as% activation=(I _(PAM) /I _(EC10-30))×100%−100%where I_(PAM) will be the L-glutamate EC₁₀₋₃₀-elicited current inpresence of various concentrations of test articles and I_(E)c₂₀ will bethe mean current elicited with L-glutamate EC₂₀. PAMconcentration-response data will be fitted to an equation of the form:% Activation=% L-glutamate EC₂₀+{(% MAX−% L-glutamateEC₂₀)/[1+([Test]/EC₅₀)^(N)]},where [Test] will be the concentration of PAM (test article), EC₅₀ willbe the concentration of PAM producing half-maximal activation, N will bethe Hill coefficient, % L-glutamate EC₂₀ will be the percentage of thecurrent Elicited with L-glutamate EC₂₀, % MAX is the percentage of thecurrent activated with the highest dose of PAM co-admitted withL-glutamate EC₂₀ and % Activation will be the percentage of the currentelicited with L-glutamate EC₁₀₋₃₀ at each PAM concentration.

The maximal amplitude of the evoked currents are measured and defined asPeak Current Amplitude (PCA).

Automated Patch-Clamp System (QPatch HTX):

In this study, HEK 293 cells stably transfected with glutamate-activatedchannels of the GRIN1/2A subtype will be used together with submaximalNMDA concentrations (300 μM NMDA, co-application with 8 μM Glycine) toinvestigate the negative allosteric modulation of the test compounds.

Cell Culture

In general, cells will be passaged at a confluence of about 80% to-90%.For electrophysiological measurements cells will be harvested at aconfluence of about 80% to 90% from sterile culture flasks containingculture complete medium. Cells will be transferred as suspension in PBSto the QPatch 16X or QPatch HTX system to the centrifuge/washerdirectly.

Standard Laboratory Conditions:

Cells will be incubated at 37° C. in a humidified atmosphere with 5% CO₂(rel. humidity about 95%).

Culture Media:

The cells will be continuously maintained in and passaged in sterileculture flasks containing a 1:1 mixture of Dulbecco's modified eaglemedium and nutrient mixture F-12 (D-MEM/F-12 1×, liquid, withL-Glutamine) supplemented with 10% fetal bovine serum, 1%Penicillin/Streptomycin solution, and 50 μM AP-5 blocker.

Antibiotics:

The complete medium as indicated above is supplemented with 100 μg/mLhygromycin, 15 μg/mL blasticidin and 1 puromycin.

Induction of Expression:

2.5 μg/mL tetracycline is added 24 h before start of experiments.

Dose Formulation

Dose levels are in terms of test compounds, as supplied. Vehicle will beadded to achieve a stock concentration of 10 mM (storage at −10° C. to−30° C.). A further stock solutions of 1.0 mM will be prepared in DMSO.Details of stock solution usage (thawing, dose formulations) will bedocumented in the raw data. The time period of stock solution usage willbe detailed in the report.

Test Compound Concentrations

Dose levels are in terms of test compounds, as supplied. Vehicle will beadded to achieve a stock concentration of 10 mM (storage at −10° C. to−30° C.). A further stock solutions of 1.0 mM will be prepared in DMSO.Details of stock solution usage (thawing, dose formulations) will bedocumented in the raw data. The time period of stock solution usage willbe detailed in the report.

One test concentration of 1.0 μM will be tested.

All test solutions will be prepared by diluting the stock solutions witheither Mg-free bath solution only or Mg-free bath solution containingNMDA (300 μM) and glycine (8.0 μM) shortly prior to theelectrophysiological experiments and kept at room temperature (19° C. to30° C.) when in use. 0.1% DMSO will be used as vehicle.

Frequency of Preparation:

For each test concentration, fresh solutions of test compounds will beprepared every day.

Stability of Dose Formulation:

All preparation times will be documented in the raw data. Anyobservations regarding instability of test compounds will be mentionedin the raw data.

Storage of Dose Formulation:

On the day of experimentation dose formulations will be maintained atroom temperature (19° C. to 30° C.) when in use.

Bath Solutions

For preparing the experiments and for formation of the giga-ohm-seal,the following standard bath solution will be used:

Sodium Chloride: 137 mM; Potassium Chloride: 4 mM; Calcium Chloride: 1.8mM; Magnesium Chloride: 1 mM; HEPES: 10 mM; D-Glucose: 10 mM; Cremophor:0.02%; pH (NaOH): 7.4

The 1× bath solution will be prepared by diluting 10× bath solutionwithout Glucose and 100× Glucose solution with water at least every 7days. Both stock solutions have been prepared prior to the experimentalstart of the present study and stored at 1° C. to 9° C. (10× bathsolution) or −10° C. to −30° (100× Glucose solution). The batchnumber(s) of the bath solution(s) used in the experiments will bedocumented in the raw data. When in use, the 1× bath solution will bekept at room temperature (19° C. to 30° C.). When not in use, the 1×bath solution will be stored at 1° C. to 9° C.

After the giga-seal was formed the following Mg-free bath solution willbe used:

Sodium Chloride: 137 mM; Potassium Chloride: 4 mM; Calcium Chloride; 2.8mM; HEPES: 10 mM; D-Glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4

This Mg-free bath solution will be prepared as a 1× solution and storedat 1° C. to 9° C. It will be prepared freshly at least every 10 days.

Intracellular Solution

The 1× intracellular solution will be thawed every day out of a frozen1× intracellular solution, which has been prepared prior to theexperimental start of the present study, aliquoted and stored at −10° C.to −30° C. When in use, the 1× intracellular solution will kept at roomtemperature (19° C. to 30° C.). Remaining 1× intracellular solution willbe stored in the fridge (1° C. to 9° C.). The 1× intracellular solutionwill include the components outlined below:

Potassium Chloride: 130 mM; Magnesium Chloride: 1 mM; Mg-ATP: 5 mM;HEPES: 10 mM; EGTA: 5 mM; pH (KOH): 7.2

Cell Treatment

For this study, cells will continuously be perfused with NMDA/Glycine,Test Compound or Test Compound/NMDA/Glycin.

In every case, at least 30-second prewash steps with a test compoundwill be performed in between applications. For details see Table Abelow.

Each experiment type will be analyzed in at least n=3 isolated cells.The NMDA and Glycine stock solutions will be prepared prior to theexperimental start of the present study, stored frozen (−10° C. to −30°C.) until the day of experimentation. Shortly prior to theelectrophysiological experiments, frozen stock solutions will be thawedand diluted.

Control: The effect of vehicle (0.1% DMSO) andD-(−)-2-Amino-5-phosphonopentanoic acid (AP-5) (100 μM) will be measuredat three cells every second week, in order to assure successfulexpression of NMDA receptors.

The 50 mM stock solution of AP-5 has been prepared prior to theexperimental start of the present study, aliquoted and stored frozen(−10° C. to −30° C.) until the day of experimentation. Shortly prior tothe electrophysiological experiments the frozen stock solution will bethawed and then diluted in Mg-free bath solution containing NMDA (300μM) and glycine (8.0 μM), to give a final perfusion concentration of 100μM.

Experimental Procedure

Cells are transferred as suspension in serum-free medium to the QPatchHTX system and kept in the cell storage tank/stirrer during experiments.All solutions applied to cells including the intracellular solution willbe maintained at room temperature (19° C. to 30° C.).

During the sealing process standard bath solution described above willbe used. All solutions applied to cells including the pipette solutionwill be maintained at room temperature (19° C. to 30° C.). Afterformation of a Gigaohm seal between the patch electrodes and transfectedindividual HEK293 cells only Mg-free bath solution will be perfused andthe cell membrane will be ruptured to assure electrical access to thecell interior (whole-cell patch-configuration). Inward currents will bemeasured upon application of 300 μM NMDA (and 8.0 μM Glycine) topatch-clamped cells for 5 sec. During the entire experiment the cellswill be voltage-clamped at a holding potential of −80 mV.

For the analysis of test compounds, NMDA receptors will be stimulated by300 μM NMDA and 8.0 μM Glycine and test compound combinations describedbelow. Thirty-second prewash steps with a test compound will beperformed in between applications.

TABLE A Application Protocol; use dependence of test compounds Appl. #Duration (s) Application 1 4 NMDA/Glycine 2 30 Bath 3 4 NMDA/Glycine 2repetitions 4 30 1 μM Test Compound 5 4 1 μM Test Compound +NMDA/Glycine 6 repetitions 6 30 Bath 7 4 NMDA/Glycine 2 repetitions

TABLE B Application Protocol; control experiments Appl. # Duration (s)Application 1 4 NMDA/Glycine 2 30 Bath 3 4 NMDA/Glycine 2 repetitions 430 Bath 5 4 NMDA/Glycine 6 repetitions 6 30 Bath 7 4 NMDA/Glycine + 100μM AP-5 2 repetitionsSynthetic Procedures

Abbreviations

THF: tetrahydrofuran; Na₂SO₄: sodium sulfate; PE: petroleum ether; DCM:dichloromethane; EtOAc: ethyl acetate; PCC: pyridinium chlorochromate;DMP: Dess-Martin periodinane; TBDPS: t-butyldiphenylsilyl; TBAF:tetra-n-butylammonium fluoride; Ts: p-toluenesulfonyl; Ac₂O: aceticanhydride; Py: pyridine; Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ph:phenyl; 9-BBN: 9-borabicyclo[3.3.1]nonane; TEA: triethylamine; BHT:2,6-di-tert-butyl-4-methylphenol; SFC: supercritical fluidchromatography; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MS: mass spectrometry; LCMS: liquidchromatography-mass spectrometry; ESI: electrospray ionization; NMR:nuclear magnetic resonance; TLC: thin layer chromatography; MeCN:acetonitrile; t-BuOK: potassium tert-butoxide.

Example 1. Synthesis of Compound 1

Synthesis of Compound A2.

To solution of Compound A1 (40 g, 110 mmol) in dry dioxane (1 L) underN₂ was added sodium methoxide (30 g, 550 mmol). The mixture was stirredat 110° C. for 16 hours, at which point TLC analysis showed the startingmaterial was consumed. The mixture was concentrated to remove roughly ⅓the volume of the solvent, and acidified with 2 M HCl to a pH of 5˜6.The solution was then extracted with DCM (3×500 mL), washed with aqueousNaHCO₃ (500 mL) and brine (500 mL), dried over Na₂SO₄, concentrated, andpurified on silica gel (PE:EtOAc:MeOH 3:1:0.1) to give Compound A2 (11g, 33.1%) as a solid.

Synthesis of Compound A3-A and Compound A3-B.

To a solution of lithium (2.5 g, 363 mmol) was added liquid ammonia(1000 mL) at −70° C. in portions. The mixture was stirred at −70° C. for30 mins until all of the lithium was dissolved. A solution of CompoundA2 (11 g, 36 mmol) and tert-BuOH (5.4 g, 72.6 mmol) in anhydroustetrahydrofuran (400 mL) was added to the reaction dropwise, and themixture was stirred for 90 mins until the reaction mixture turned lightyellow, at which point TLC analysis indicated the starting material wasconsumed. Ammonium chloride (15 g) was then added, and the mixture wasconcentrated. The resulting residue was extracted with with 0.5N HCl(500 mL) and dichloromethane (500 mL×2), and the combined organic layerswere washed with saturated NaHCO₃, dried over Na₂SO₄, filtered, andconcentrated to give a mixture of Compound A3-A and Compound A3-B (10 g,impure) which was used directly in the next step without furtherpurification.

Synthesis of Compound A4.

To a solution of Compound A3-A and Compound A3-B (10 g crude, 27.9 mmol)in anhydrous dichloromethane (100 mL) was added PCC (17 g, 66 mmol) andsilica gel (17 g). After stirring at 25° C. for 2 h, TLC analysisindicated the starting material was consumed. The resulting solution wasconcentrated and purified by silica gel (PE:EtOAc 5:1 to 2:1) to affordCompound A4 (4.6 g, 46%) as a solid.

Synthesis of Compound A5.

To a solution of Compound A4 (4.6 g, 15 mmol) in THF (50 mL) was slowlyadded a solution of LiAlH(t-BuO)₃ (4.2 mg, 17 mmol) in THF (20 mL) underN₂ at −40° C. The reaction solution was stirred at −40° C. for 15 min,at which point TLC analysis indicated the starting material wasconsumed. The mixture was quenched with saturated NH₄Cl solution (50 mL)and extracted with EtOAc (50 mL×2). The organic layers were combined,dried over Na₂SO₄, concentrated, and purified by combi-flash (PE:EA100%-50%) to afford Compound A5 (2.8 g, 61%) as a solid.

Synthesis of Compound A6.

To a suspension of bromo(ethyl)-triphenylphosphorane (17 g, 46 mmol) inanhydrous THF (100 mL) under N₂ at 20° C. was added t-BuOK (1 M in THF,46 mL, 46 mmol). The mixture was stirred at 60° C. for 1 h, followed bythe addition of a solution of Compound A5 (2.8 g, 9.19 mmol) inanhydrous THF (50 mL). The resultant mixture was stirred at 60° C. for16 h, at which point TLC analysis indicated the starting material wasconsumed. The reaction mixture was quenched with aqueous NH₄Cl (100 mL),extracted with EtOAc (100 mL×3), dried over Na₂SO₄, filtered,concentrated, and purified by silica gel (PE:EA:DCM 10:1:1) to giveCompound A7 (2.2 g, crude) as a solid.

Synthesis of Compound A7.

To a solution of Compound A6 in THF (10 mL) was added LiAlH₄ (110 mg,3.1 mmol). The reaction mixture was stirred at 15° C. for 30 minutes, atwhich point TLC analysis indicated the reaction was complete. SaturatedNH₄Cl (0.2 mL) was added to the reaction, and the mixture was filtered.The filterate was concentrated to give a residue, to which was addedsaturated NaCl solution (10 mL), followed by extraction with DCM (3×5mL). The combined organic phase was dried over Na₂SO₄ and concentratedto afford Compound A7 (0.4 g, 80%) as a solid.

Synthesis of Compound A8.

To a solution of Compound A7 (0.4 g, 1.3 mmol) and methyl propiolate(260 mg, 3.1 mmol) in DCM (10 mL) was added Et₂AlCl (3.8 mL, 3.8 mmol,1M in hexane) under N₂ at 15° C. The reaction mixture was stirred at 15°C. for 16 hours, at which point TLC analysis indicated the reaction wascomplete. The reaction mixture was quenched with a citric acid solution(10 mL). The resulting solution was washed with DCM (10 mL×2). Theorganic layers were combined, dried Na₂SO₄, concentrated, and purifiedby combi-flash (PE:EA=100%−65%) to give desired Compound A8 as a solid.

Synthesis of Compound A9.

To a solution of Compound A8 in EtOAc (10 mL) was added Pd/C (wet, 10%,0.02 g). After degassing three times with H₂, the reaction mixture wasstirred for 16 hours at 15° C. under H₂ (15 Psi), after which point LCMSanalysis indicated the reaction was complete. The mixture was filteredand the filtrate was concentrated to give crude Compound A9 as a solid,which was used in next step directly without further purification.

Synthesis of Compound A10.

To a solution of Compound A9 (0.15 g, 0.37 mmol) in THF (10 mL) wasadded MeLi (1.2 mL, 1.8 mmol, 1.6 M in diethyl ether). The reactionsolution was stirred at 15° C. for 1 hour, at which point TLC analysisindicated the reaction was complete. The mixture was quenchend withNH₄Cl solution (10 mL) and extracted with EtOAc (10 mL×2), followed bydrying the combined organic phase over Na₂SO₄ and concentrating to giveCompound A10 (0.15 g) as a solid.

Synthesis of Compound A11.

To a solution of Compound A10 (150 mg, 0.37 mmol) in DCM (10 mL) wasadded silicon grease (150 mg) and PCC (160 mg, 0.74 mmol). The resultingreaction mixture was stirred at 15° C. for 2 hours, after which TLCanalysis indicated the reaction was complete. The mixture was filtered,concentrated, and purified by combi-flash (PE:EA=100%-75%) to giveCompound A11 (130 mg, 88%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ2.82-2.71 (m, 1H), 2.60-2.38 (m, 3H), 2.35-2.20 (m, 3H), 2.15-1.90 (m,3H), 1.88-1.02 (m, 23H), 0.88 (d, J=5.8 Hz, 6H), 0.64 (s, 3H).

Synthesis of Compound 1.

To a solution of MAD (0.37 mmol) in toluene (5 mL) was added a solutionof Compound A11 (50 mg, 0.12 mmol) in toluene (1 mL) under N₂ at −70° C.The mixture was stirred at −70° C. for 30 minutes, followed by additionof MeMgBr (0.12 mL, 0.37 mmol, 3M in ether) under N₂. The resultingmixture was stirred at −70° C. for 1 hour, at which point TLC indicatedthe reaction was complete. The mixture was quenched with a saturated acitric acid solution (10 mL) and extracted with EtOAc (5 mL×2). Thecombined organic phase was dried over Na₂SO₄, concentrated, and purifiedby combi-flash (PE:EtOAc=100%−70%) to give Compound 1 (6.5 mg, 13%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 2.53-2.50 (m, 1H), 2.45-2.35 (m,1H), 2.25-2.22 (m, 2H), 2.10-1.90 (m, 2H), 1.80-1.05 (m, 26H), 1.00 (s,3H), 0.95-0.80 (m, 8H), 0.62 (s, 3H). LCMS MS ESI calcd. for C₂₇H₄₇O₃[M+H]⁺419, found 401[M+H−18]⁺.

Example 2. Synthesis of Compound 2

Synthesis of Compound 2.

To a solution of Compound A11 (50 mg, 0.12 mmol) in THF (2 mL) was addedLiAlH(t-BuO)₃ (47.2 mg, 0.186 mmol). The reaction mixture was stirred at25° C. under N₂ for 30 min, after which TLC indicated the reaction wascomplete. The mixture was then quenched with saturated with NH₄Clsolution (5 mL) and extracted with EtOAc (3×2 mL). The combined organicphase was dried over Na₂SO₄, concentrated, and purified by silica gel toafford Compound 2 (7.5 mg, 15%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 3.65-3.49 (m, 1H), 2.50 (s, 2H), 2.29-2.15 (m, 1H), 2.09-1.90(m, 1H), 1.85-0.97 (m, 32H), 0.93-0.76 (m, 4H), 0.62 (s, 3H). LCMS ESIcalcd. for C₂₆H₄₅O₃ [M+H]⁺405, found 387 [M+H−18]⁺.

Example 3. Synthesis of Compound 3

Synthesis of B1.

To a solution of A1 (50 g, 14 mmol) in py (500 mL) was added Ac₂O (21 g,210 mmol) dropwise at 0° C. The reaction was stirred at 25° C. for 24hrs. The mixture was poured into 4 L of water. After stirring at 25° C.for 0.5 h, the mixture was filtered. The solid was washed with HCl (1 L,1 M) and dried to give B1 (55 g, 99%) as a solid. ¹H NMR (400 MHz,CDCl₃) δ 5.69 (s, 1H), 5.03 (d, J=17.6 Hz, 1H), 4.85 (d, J=17.6 Hz, 1H),4.51-4.44 (brs, 1H), 2.85-2.70 (m, 1H), 2.55-2.40 (m, 2H), 2.39-2.32 (m,1H), 2.30-1.95 (m, 9H), 1.91-1.79 (m, 2H), 1.75-1.66 (m, 2H), 1.52-1.40(m, 5H), 1.20-0.97 (m, 3H), 0.97 (s, 3H).

Synthesis of B2.

To a solution of B1 (55 g, 14 mmol) in py (1000 mL) was added MgSO4 (35g, 320 mmol) and PCC (35 g, 160 mmol) at 0° C. The reaction solution wasstirred at 25° C. for 12 hrs. The mixture was filtered through Celite.The mixture was poured into 2 L of water to give a dark red suspension.After filtration, the filter cake was washed by 1M HCl (2×500 mL) andH₂O (2×500 mL), and dried under vacuum at 0° C. to give B2 (38 g, 69%)as a brown powder. ¹H NMR (400 MHz, CDCl₃) δ 5.73 (s, 1H), 5.13 (d,J=17.6 Hz, 1H), 4.64 (d, J=17.6 Hz, 1H), 3.05-2.98 (m, 1H), 2.92-2.85(m, 1H), 2.85-2.70 (m, 2H), 2.55-2.21 (m, 5H), 2.16 (s, 3H), 2.02-1.88(m, 3H), 1.87-1.45 (m, 5H), 1.48 (s, 3H), 1.38-1.21 (m, 1H), 0.66 (s,3H).

LCMS Rt=0.601 min in 2.0 min chromatography, 30-90_2 MIN_E.M, purity77%, MS ESI calcd. for C₂₃H₃₁O₆ [M+H]+403, found 403.

Synthesis of B3.

To a solution of B2 (38 g, 94 mmol) in Ac₂O (600 mL, 6.3 mol) was addedp-TsOH (19 g, 110 mmol) at 20° C. for 6 hrs. The mixture was poured into4 L of ice water and stirred at 20° C. for 48 hrs until a solid formed.The filtered cake was concentrated in vacuum at 80° C. to give 35 g ofimpure product as yellow solid. The crude product was purified by columnchromatography (PE:EA=3:1-2:1) to give B3 (29.6 g, 64%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.70-5.65 (m, 1H), 5.39-5.33 (m, 1H),4.81-4.68 (m 2H), 2.94-2.82 (m, 2H), 2.71-2.63 (m, 1H), 2.56-2.25 (m,4H), 2.20-1.82 (m, 15H), 1.55-1.44 (m, 1H), 1.31-1.20 (m, 1H), 1.18 (s,3H), 0.72 (s, 3H).

LCMS Rt=0.981 min in 2.0 min chromatography, 30-90_2 MIN_E.M, purity61%, MS ESI calcd. for C₂₅H₃₁O₆ [M+H-HOAc]⁺427, found 427.

Syntheses of B4 and B5.

To a solution of B3 (15 g, 31 mmol) in EtOH (600 mL), MeOH (60 mL) andDCM (50 mL) was slowly added NaBH₄ (40 g, 1.1 mol) at 0° C. The reactionmixture was stirred for 1 h at 0° C., then at 20° C. for 15 hrs. Thereaction mixture was quenched by adding 600 mL of 1M HCl at 0° C. Themixture was extracted by EtOAc (2×1.5 L). The organic phase was washedwith Sat. NaHCO₃ (300 mL), brine (200 mL), dried over Na₂SO₄, filteredand concentrated to give 9.3 g of crude product as a white solid. 9.3 gof crude product B4 was dissolved in 400 mL of MeOH. To this solutionwas added periodic acid (7 g, 36 mmol) at 0° C. After stirring for 6 hrsat 20° C., the mixture was quenched by 200 mL of 1 M HCl and extractedby 1.5 L of EtOAc. The organic phase was washed with 500 mL of saturatedNaHCO₃, 200 mL of brine, dried over Na₂SO₄, filtered and concentrated togive B5 (6.3 g, crude) as a foaming oil, which was used for the nextstep without purification.

¹H NMR (400 MHz, CDCl₃) δ 5.42-5.23 (m, 1H), 3.57-3.48 (m, 1H),3.39-3.32 (m, 1H), 2.78-2.41 (m, 2H), 2.37-2.10 (m, 4H), 1.95-1.62 (m,6H), 1.46-0.72 (m, 11H).

LCMS Rt=0.440 min in 2.0 min chromatography, 30-90_2 MIN_E.M, purity100%, MS ESI calcd. for C₁₉H₂₅O₂ [M+H-H₂O]⁺285, found 285.

Synthesis B6.

To a slurry of Ph₃PEtBr (23 g, 62 mmol) in THF (150 mL) was added t-BuOK(7.2 g, 64 mmol) under N₂. After addition, the mixture was stirred at50° C. for 30 minutes. B5 (6.3 g, 21 mmol) in THF (50 mL) was added. Themixture was stirred at 50° C. for 2 hrs. The mixture was quenched withSat. NH₄Cl (200 mL) and extracted with EtOAc (2×400 mL). The combinedorganic phase was washed with brine (40 mL), dried over Na₂SO₄,filtered, concentrated and purified by flash column (0-20% of EtOAc inPE) to give B6 (2.7 g, impure) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 5.39-5.33 (m, 1H), 5.24-5.16 (m, 1H),3.56-3.46 (m, 1H), 2.98 (d, J=13.6 Hz, 1H), 2.58-2.06 (m, 6H), 1.99-0.92(m, 17H), 0.86 (s, 3H).

Synthesis of B7.

To a solution of B6 (2.75 g, 8.74 mmol) in THF (100 mL) was added LiAlH₄(0.7 g, 18 mmol) in portions. The reaction mixture was stirred at 20° C.for 30 minutes. The reaction was quenched by 150 mL of 1M HCl at 0° C.and extracted with 400 mL of EtOAc. After the layers were separated, theorganic phase was washed with 100 mL of Sat. NaHCO₃, 100 mL of brine,dried over NaSO₄ and concentrated. The residue was purified by flashcolumn eluted with PE:EtOAc=20:1 to 4:1 to give B7 (1.7 g, 60%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 5.28-5.24 (m, 1H), 5.15-5.06 (m, 1H),4.45-4.38 (m, 1H), 3.60-3.46 (m, 1H), 2.50-2.35 (m, 2H), 2.34-2.25 (m,2H), 2.25-2.14 (m, 2H), 2.04-1.78 (m, 4H), 1.73-1.61 (m, 5H), 1.45-1.04(m, 13H).

Synthesis of B8.

To a solution of B7 (1.7 g, 5.2 mmol) and methyl propionate (1.3 g, 16mmol) in DCM (70 mL) was added Et₂AlCl (16 mL, 16 mmol, 1 M in hexane)under N₂ at −20° C. The mixture was stirred at 20° C. for 4 hrs andquenched by 20 mL of Sat.NaHCO₃, 50 mL of saturated critic acid at 0° C.The mixture was extracted with 300 mL of EtOAc. The organic phase waswashed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography and eluted withPE:EtOAc=20:1 to 2:1 to give B8 (1.4 g, 67%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.92 (dd, J=15.6, 7.9 Hz, 1H), 5.83 (dd,J=15.7, 1.0 Hz, 1H), 5.44-5.38 (m, 1H), 5.27-5.23 (m, 1H), 4.46-4.37 (m,1H), 3.73 (s, 3H), 3.60-3.43 (m, 1H), 3.10-2.97 (m, 1H), 2.33-2.25 (m,2H), 2.22-1.82 (m, 8H), 1.74-1.62 (m, 3H), 1.36-1.03 (m, 13H).

Synthesis of B9.

To a solution of B8 (500 mg, 1.2 mmol) in DCM (10 mL) was added TBDPSCl(510 mg, 1.9 mmol) and imidazole (170 mg, 2.5 mmol). The mixture wasstirred at 15° C. for 16 hrs. The mixture was quenched with water (20mL) and extracted with DCM (2×10 mL). The combined organic phase wasdried over Na₂SO₄, filtered, concentrated and purified by combi-flash(5% of EtOAc in PE) to give B9 (700 mg, 88%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 4H), 7.45-7.35 (m, 6H),6.95-6.85 (m, 1H), 5.85-5.75 (m, 1H), 5.45-5.35 (m, 1H), 5.05-4.95 (m,1H), 4.35-4.25 (m, 1H), 3.72 (s, 3H), 3.55-3.45 (m, 1H), 3.05-2.95 (m,1H), 2.45-2.35 (m, 1H), 2.15-1.81 (m, 7H), 1.80-1.58 (m, 6H), 1.30-1.16(m, 5H), 1.15-1.11 (m, 3H), 1.10-0.95 (m, 10H).

Synthesis of B10.

To a solution of B9 (700 mg, 1.1 mmol) in MeOH (20 mL) and EtOAc (10 mL)was added Pt/C (50 mg). After degassing for three times with H₂, thereaction mixture was stirred for 32 hrs at 20° C. under H₂ balloon. Themixture was filtered and concentrated to give B10 (640 mg, 91%) asanoil.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 4H), 7.45-7.35 (m, 6H),5.07-5.04 (m, 1H), 4.27-4.24 (m, 1H), 3.69 (s, 3H), 3.60-3.50 (m, 1H),2.45-2.05 (m, 8H), 1.90-1.58 (m, 8H), 1.56-1.21 (m, 9H), 1.20-0.82 (m,15H).

Synthesis of B11.

To a solution of B10 (640 mg, 1.0 mmol) in THF (20 mL) was added MeLi(3.1 mL, 5.0 mmol, 1.6 M in THF) at 0° C. under N₂. After addition, thereaction mixture was stirred at 20° C. for 30 minutes. The mixture wasquenched with saturated NH₄Cl solution (30 mL) and extracted with EtOAc(2×15 mL). The combined organic phase was dried over Na₂SO₄, filtered,concentrated and purified by combi-flash (0-10% of EtOAc in PE) to giveB11 (410 mg, 64%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 4H), 7.45-7.35 (m, 6H),5.07-5.04 (m, 1H), 4.27-4.24 (m, 1H), 3.60-3.50 (m, 1H), 2.45-2.35 (m,1H), 2.20-2.00 (m, 2H), 1.90-1.58 (m, 10H), 1.56-1.21 (m, 14H),1.20-1.06 (m, 9H), 1.05-0.85 (m, 13H).

Synthesis of Compound 3.

B11 (350 mg, 0.54 mmol) was dissolved in TBAF (5 mL, 1M in THF). Themixture was stirred at 70° C. for 24 hrs. The reaction was quenched withsaturated NH₄Cl solution (10 mL) and extracted with EtOAc (2×10 mL). Thecombined organic phase was dried over Na₂SO₄, filtered, concentrated andpurified by combi-flash (0-20% of EtOAc in PE) to give Compound 3 (200mg, 91%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.26-5.22 (m, 1H), 4.35-4.31 (m, 1H),3.55-3.45 (m, 1H), 2.32-2.29 (m, 2H), 2.20-2.10 (m, 2H), 2.05-1.95 (m,1H), 1.94-1.75 (m, 3H), 1.70-1.41 (m, 4H), 1.40-0.85 (m, 29H).

LCMS Rt=1.245 min in 2.0 min chromatography, 10-80 AB, purity 100%, MSESI calcd. for C₂₆H₄₄O₃Na [M+Na]⁺427, found 427.

Example 4. Synthesis of Compound 4

Synthesis of C1.

To a solution of B11 (60 mg, 0.093 mmol) in DCM (5 mL) was added DMP (78mg, 0.19 mmol). The mixture was stirred at 20° C. for 16 hrs. Themixture was quenched with saturated Na₂SO₃ and saturated NaHCO₃(V:V=1:1,10 mL) and extracted with DCM (2×10 mL). The combined organic phase wasdried over Na₂SO₄, filtered and concentrated to give C1 (65 mg, crude)as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.68-7.66 (m, 4H), 7.45-7.35 (m, 6H),5.07-5.04 (m, 1H), 3.60-3.50 (m, 1H), 2.65-2.46 (m, 2H), 2.45-1.95 (m,7H), 1.80-0.81 (m, 34H), 0.80-0.65 (m, 2H), 0.62 (s, 3H).

Synthesis of Compound 4.

C1 (60 mg, 0.094 mmol) was dissolved in TBAF (3 mL) and the reaction wasstirred at 70° C. for 3 hrs. The reaction was quenched with saturatedNH₄Cl solution (10 mL) and extracted with EtOAc (2×10 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, concentrated and purifiedby combi-flash (0-20% of EtOAc in PE) to give Compound 4 (10 mg, 27%) asa solid.

¹H NMR (400 MHz, CDCl₃) δ 5.35-5.30 (m, 1H), 3.55-3.45 (m, 1H),2.70-2.60 (m, 2H), 2.30-1.95 (m, 5H), 1.94-1.58 (m, 7H), 1.56-1.05 (m,17H), 1.04-0.75 (m, 6H), 0.65 (s, 3H).

LCMS Rt=1.227 min in 2.0 min chromatography, 10-80 AB, purity 100%, MSESI calcd. for C₂₆H₄₁O₂ [M+H-H₂O]⁺385, found 385.

Example 4. Synthesis of Compound 5

Synthesis of D2.

t-BuOH (150 mL) was charged into a three-neck round bottom flask undernitrogen at 35° C. and stirred under nitrogen gas bubbling for 10 mins.t-BuOK (20 g, 180 mmol) was added to the mixture and stirred undernitrogen gas bubbling for 15 mins D1 (5 g, 17 mmol) was added to theabove mixture and stirred under nitrogen gas bubbling at 35° C. for 1.5hrs. The reaction mixture was poured into 10% aqueous acetic acid (250mL) and stirred for 15 mins Water (100 mL) was added and stirred for 30mins. The pH of the mixture was adjusted to 7-8 with sodium bicarbonate(28 g). The mixture was stirred for 30 mins. The precipitated solid wasfiltered off, washed with water and suction dried. The product obtainedwas dissolved in DCM, dried over anhydrous sodium sulfate, filtered andconcentrated under a water bath maintained at 40° C. to give D2 (3.6 g,72%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.45-5.40 (m, 1H), 4.22-4.10 (m, 1H),3.40-3.30 (m, 1H), 2.90-2.80 (m, 2H), 2.60-2.45 (m, 2H), 2.33-2.27 (m,1H), 2.20-2.08 (m, 3H), 2.02-1.90 (m, 1H), 1.75-1.66 (m, 2H), 1.65-1.50(m, 2H), 1.45-1.30 (m, 5H), 1.20-1.10 (m, 2H), 0.94 (s, 3H).

To a solution of BHT (16 g, 71 mmol) in anhydrous toluene (100 mL) undernitrogen at 0° C. was added Me₃Al (2 M in toluene, 18 mL, 36 mmol)dropwise. The mixture was warmed to 20° C. gradually and stirred for 1hr. To the mixture was added a solution of D2 (3.6 g, 12 mmol) intoluene (20 mL) and DCM (20 mL) dropwise. The resulting mixture wasstirred at −78° C. for 30 min. EtMgBr (3 M in diethyl ether, 12 mL, and36 mmol) was added to the above mixture dropwise, and the reactionmixture was stirred at −78° C. for 3 hrs. The reaction was quenched withsaturated aqueous citric acid and the aqueous layer was washed withEtOAc (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by column chromatography on silica gel(PE/EtOAc/THF=4/1/1) to give D3 (3 g, 76%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.40-5.38 (m, 1H), 4.20-4.10 (m, 1H),2.55-2.40 (m, 3H), 2.20-2.05 (m, 4H), 2.00-1.90 (m, 1H), 1.75-1.65 (m,2H), 1.64-1.60 (m, 7H), 1.29-1.16 (m, 6H), 1.15-1.05 (m, 1H), 0.95-0.87(m, 3H), 0.86-0.80 (m, 3H).

Synthesis of D4.

To a suspension of bromo(ethyl)triphenylphosphorane (10 g, 27 mmol) inanhydrous THF (100 mL) under nitrogen at 25° C. was added potassiumt-butoxide (3.0 g, 27 mmol) in one portion. The color of the mixtureturned deep orange. The mixture was warmed to 40° C., and D3 (3 g, 9.0mmol) was added to the mixture in one portion. The resulting mixture wasstirred at 40° C. for 16 hrs. The reaction mixture was poured into icewater (100 mL) and extracted with EtOAc (2×100 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (PE/EtOAc=8/1) to give D4 (2.1 g, 68%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.37-5.35 (m, 1H), 5.20-5.10 (m, 1H),4.20-4.05 (m, 1H), 2.65-2.57 (m, 1H), 2.45-2.37 (m, 3H), 2.28-2.18 (m,1H), 2.08-1.98 (m, 2H), 1.70-1.61 (m, 8H), 1.60-1.35 (m, 3H), 1.25-1.10(m, 7H), 1.08-0.92 (m, 2H), 0.90-0.87 (m, 3H), 0.86-0.80 (m, 3H).

Synthesis of D5.

To a solution of D4 (1 g, 2.9 mmol) in DCM (15 mL) was added silica gel(1.4 g) and PCC (1.3 mg, 5.8 mmol) at 25° C. The reaction was stirred at25° C. for 3 hrs. The reaction was filtered and concentrated in vacuumto give crude product which was purified by combi-flash (0%-12% of EtOAcin PE) to give D5 (960 mg, 97%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.26 (m, 1H), 5.24-5.19 (m, 1H),3.00-2.95 (m, 1H), 2.70-2.60 (m, 1H), 2.55-2.30 (m, 4H), 2.20-2.16 (m,1H), 2.07-2.01 (m, 1H), 1.90-1.70 (m, 5H), 1.68-1.55 (m, 5H), 1.55-1.25(m, 4H), 1.22 (s, 3H), 1.00-0.90 (m, 1H), 0.80-0.80 (m, 6H).

Synthesis of D6.

To a solution of D5 (870 mg, 2.5 mmol) in THF (30 mL) was added LiAlH₄(190 mg, 5.1 mmol) at 0° C. The reaction was stirred at 20° C. for 20mins. The reaction was quenched with H₂O (2 mL) and adjusted with HCl(20 mL, 1N) until the solution became clear. The mixture was extractedwith EtOAc (3×20 mL). The combined organic phase was washed withsaturated NaHCO₃ (50 mL), dried over Na₂SO₄, filtered and concentratedin vacuum to give crude product D6 (860 mg) as a solid which was usedfor next step without further purification.

Synthesis of D7.

To a solution of D6 (5.5 g, 16 mmol) in THF (100 mL) was added 9-BBNdimer (7.8 g, 32 mmol) at 15° C. under N₂. After stirring at 50° C. for1 hour, the mixture was cooled to 15° C. NaOH solution (32 mL, 5 M, 160mmol) was added dropwise below 15° C., followed an addition of H₂O₂ (18g, 30%, 160 mmol), during which time, the inner temperature wasmaintained below 15° C. The mixture was poured into water (1000 mL) andfiltered to give crude D7 (10 g) as a solid, which was used in the nextstep directly.

¹H NMR (400 MHz, CDCl₃) δ 5.21-5.15 (m, 1H), 4.40-4.29 (m, 1H),3.77-3.66 (m, 1H), 2.46-2.38 (m, 1H), 2.29-2.12 (m, 1H), 2.09-2.00 (m,2H), 1.98-1.78 (m, 4H), 1.77-1.68 (m, 2H), 1.62-1.53 (m, 2H), 1.47-1.32(m, 4H), 1.31-1.27 (m, 4H), 1.26-1.18 (m, 5H), 1.17-1.09 (m, 1H),1.08-0.99 (m, 3H), 0.97-0.89 (m, 3H), 0.88-0.82 (m, 3H).

Synthesis of D8.

To a solution of D7 (10 g, 27 mmol) in DCM (500 mL) was added DMP (23 g,55 mmol). After stirring at 15° C. for 10 min, the reaction mixture wasquenched with saturated NaHCO₃ solution (500 mL) until the pH of theaqueous layer became about 9. The mixture was filtered. The DCM layerwas separated and the aqueous phase was washed with DCM (200 mL). Thecombined organic layers were washed with saturated Na₂S₂O₃ aqueous(3×400 mL), saturated NaHCO₃ (400 mL), and brine (400 mL). The solutionwas then dried over Na₂SO₄, filtered and concentrated to give a crude,which was purified by combi-flash (0-30% of EtOAc in PE) to give D8 (3.5g, 35%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.25 (m, 1H), 2.75-2.65 (m, 2H),2.63-2.55 (m, 1H), 2.48-2.42 (m, 1H), 2.39-2.31 (m, 1H), 2.29-2.18 (m,1H), 2.15-2.08 (m, 4H), 2.06-2.02 (m, 1H), 1.89-1.72 (m, 6H), 1.67-1.60(m, 2H), 1.46-1.30 (m, 4H), 1.21 (s, 3H), 1.03-0.93 (m, 1H), 0.88-0.80(m, 3H), 0.60 (s, 3H).

Synthesis of D9.

To a suspension of MePh₃PBr (6.2 g, 18 mmol) in THF (100 mL) was addedt-BuOK (2.0 g, 18 mmol). After stirring at 40° C. for 10 minutes, theWittig reagent was slowly added dropwise to a solution of D8 (3.2 g, 8.8mmol) in THF (50 mL) at 15° C. After addition, the mixture was quenchedwith NH₄Cl (200 mL) and extracted with EtOAc (3×50 mL). The combinedorganic phase was dried over Na₂SO₄, filtered, concentrated and purifiedby combi-flash (0-25% of EtOAc in PE) to give D9 (2.9 g, 92%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 5.36-5.18 (m, 1H), 4.89 (s, 1H), 4.71 (s, 1H),2.65-2.46 (m, 2H), 2.40-2.31 (m, 1H), 2.30-2.20 (m, 2H), 2.16-1.98 (m,2H), 1.91-1.98 (m, 4H), 1.76-1.62 (m, 5H), 1.51-1.32 (m, 4H), 1.31-1.13(m, 6H), 1.04-0.93 (m, 1H), 0.88-0.82 (m, 3H), 0.55 (s, 3H).

Synthesis of D10.

To a mixture of D9 (3.2 g, 9.0 mmol) in THF (80 mL) was added 9-BBNdimer (4.4 g, 18 mmol) at 15° C. under N₂. After stirring at 50° C. for1 hour, the mixture was cooled to 15° C. NaOH solution (18 mL, 5 M, 90mmol) was added dropwise below 15° C., followed by an addition of H₂O₂(10 g, 30%, 90 mmol) below 15° C. The mixture was extracted with EtOAc(2×50 mL). The combined organic phase was washed with saturated Na₂S₂O₃(3×100 mL), dried over Na₂SO₄, filtered and concentrated to give crudeD10 (6 g) as a solid, which was used in next step directly.

¹H NMR (400 MHz, CDCl₃) δ 5.24-5.09 (m, 1H), 4.44-4.28 (m, 1H),3.73-3.59 (m, 1H), 3.44-3.30 (m, 1H), 2.48-2.32 (m, 1H), 2.22-2.08 (m,2H), 2.06-2.00 (m, 1H), 1.95-1.77 (m, 4H), 1.75-1.63 (m, 4H), 1.50-1.33(m, 5H), 1.29-1.13 (m, 8H), 1.09-1.00 (m, 5H), 0.94 (s, 3H), 0.89-0.82(m, 3H).

Synthesis of D11.

To a solution of D10 (6 g, 16 mmol) in DCM (200 L) was added1-methyl-1H-imidazole (2.0 g, 24 mmol) and TEA (3.2 g, 32 mmol) at 20°C. TsCl (6.1 g, 32 mmol) was added into the above solution. Afterstirring at 20° C. for 2 hours, the mixture was washed with water (2×100mL), dried over Na₂SO₄, filtered, concentrated and purified bycombi-flash (0-40% of EtOAc in PE) to give D11 (2.8 g, 59% yield for 2steps) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.81-7.74 (m, 2H), 7.38-7.31 (m, 2H),0.5.21-5.14 (m, 1H), 4.35-4.29 (m, 1H), 3.97-3.92 (m, 1H), 3.84-3.76 (m,1H), 2.49-2.35 (m, 4H), 2.18-2.00 (m, 3H), 1.91-1.73 (m, 3H), 1.72-1.58(m, 5H), 1.50-1.31 (m, 4H), 1.28 (s, 3H), 1.26-1.09 (m, 5H), 1.05-0.92(m, 5H), 0.91-0.80 (m, 6H).

Synthesis of D12.

To a solution of D11 (2.8 g, 5.3 mmol) in DMF (20 mL) was added KI (4.4g, 26 mol) at 15° C. After stirring at 60° C. for 1 hour, sodiumbenzenesulfinate (5.2 g, 32 mmol) was added in one portion and themixture was heated at 60° C. for 2 h. The mixture was then quenched withsaturated NH₄Cl (50 mL) and extracted with EtOAc (2×30 mL). The combinedorganic phase was washed with LiCl (3% in water, 2×50 mL), dried overNa₂SO₄, filtered, concentrated and purified by combi-flash (0-30% ofEtOAc in PE) to give D12 (1.6 g, 61%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.95-7.88 (m, 2H), 7.67-7.54 (m, 3H),5.19-5.14 (m, 1H), 4.34-4.27 (m, 1H), 3.17-3.08 (m, 1H), 2.89-2.80 (m,1H), 2.643-2.36 (m, 1H), 2.16-2.06 (m, 3H), 2.04-1.99 (m, 1H), 1.92-1.81(m, 2H), 1.76-1.56 (m, 4H), 1.48-1.30 (m, 3H), 1.27 (s, 3H), 1.26-1.05(m, 9H), 1.04-0.94 (m, 3H), 0.88 (s, 3H), 0.86-0.82 (m, 3H).

Synthesis of D13.

To a solution of D12 (1.2 g, 2.4 mmol) in DCM (30 mL) was added DMP (2.0g, 4.8 mmol). The reaction mixture was stirred at 15° C. for 10 min. Thereaction mixture was then quenched with saturated NaHCO₃ aqueous (50 mL)until pH of the aqueous layer became about 9 and then filtered. Theorganic layer was separated and the aqueous phase was washed with DCM(20 mL). The combined organic phase was washed with saturated Na₂S₂O₃aqueous (3×40 mL), saturated NaHCO₃ (40 mL), brine (40 mL), dried overNa₂SO₄, filtered and concentrated to give crude D13 (1.1 g, 92%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ 7.95-7.88 (m, 2H), 7.70-7.54 (m, 3H),5.29-5.24 (m, 1H), 3.16-3.06 (m, 1H), 2.92-2.83 (m, 1H), 2.65-2.51 (m,2H), 2.38-2.30 (m, 1H), 2.25-2.16 (m, 1H), 2.14-1.98 (m, 3H), 1.95-1.85(m, 1H), 1.82-1.58 (m, 7H), 1.50-1.34 (m, 3H), 1.27-1.16 (m, 9H),1.01-0.91 (m, 1H), 0.87-0.80 (m, 3H), 0.64 (s, 3H).

Synthesis of D14.

To a solution of diisopropylamine (160 mg, 1.60 mmol) in THF (0.5 mL)was added n-BuLi (0.56 mL, 2.5 M in hexane, 1.40 mmol) at −70° C. underN₂. The mixture was then stirred at 15° C. for 10 minutes. A solution ofD13 (200 mg, 0.40 mmol) in THF (1.5 mL) was added at −70° C. Afterstirring at −70° C. for 1 h, 2,2-dimethyloxirane (43 mg, 0.60 mmol) wasadded. The mixture was stirred at −70° C. for another 1 h, after whichtime the mixture was warmed to 15° C. and stirred for 16 hrs. Themixture was quenched with NH₄Cl (30 mL, sat. aq.) and extracted withEtOAc (2×20 mL). The organic layer was separated, dried over Na₂SO₄,filtered, and concentrated to give D14 (200 mg, crude) as a solid, whichwas used for the next step directly.

Synthesis of Compound 5.

To a solution of D14 (200 mg, 0.35 mmol) in MeOH (30 mL) was added NiCl₂(8.8 mg, 0.070 mmol) and Mg powder (340 mg, 14 mmol) at 65° C. in oneportion. After stirring at 65° C. for 10 minutes, another batch of Mgpowder (170 mg, 7 mmol) was added in one portion. The mixture wasstirred at 65° C. for another 10 minutes, then quenched with HCl (20 mL,2N) until the reaction became clear and extracted with EtOAc (3×10 mL).The combined organic layer was washed with sat. NH₄Cl (30 mL), driedover Na₂SO₄, filtered, concentrated and purified by silica gelchromatography (0-15% of EtOAc in PE) to give impure Compound 5 (30 mg,20%) as a white solid, which was further separated by SFC (column: OD(250 mm*30 mm, 5 um)), gradient: 40-40% B (A=0.05% NH₃/H₂O, B=MeOH),flow rate: 50 ml/min) to give pure Compound 5 (10 mg, 7%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.31-5.25 (m, 1H), 2.67-2.52 (m, 2H),2.38-2.32 (m, 1H), 2.25-2.18 (m, 1H), 2.15-1.94 (m, 3H), 1.87-1.55 (m,8H), 1.54-1.27 (m, 8H), 1.26-1.21 (m, 4H), 1.20-1.11 (m, 8H), 1.03-0.88(m, 4H), 0.87-0.81 (m, 3H), 0.65 (s, 3H).

LCMS Rt=1.111 min in 2.0 min chromatography, 30-90AB_E, purity 100%, MSESI calcd. for C₂₈H₄₅O₂ [M+H-H₂O]⁺413, found 413.

Example 5. Synthesis of Compound 6

Synthesis of E1.

To a solution of diisopropylamine (160 mg, 1.60 mmol) in THF (0.5 mL)was added n-BuLi (0.56 mL, 2.5 M in hexane, 1.4 mmol) at −70° C. underN₂. The mixture was then stirred at 15° C. for 10 minutes. A solution ofD13 (200 mg, 0.40 mmol) in THF (1.5 mL) was added at −70° C. Afterstirring at −70° C. for 1 h, (S)-2-isopropyloxirane (52 mg, 0.60 mmol)was added at −70° C. The mixture was stirred at −70° C. for another 1 h,warmed to 15° C. and stirred for 16 hrs. The reaction mixture wasquenched with saturated NH₄Cl (50 mL, aq.) and extracted with EtOAc(2×30 mL). The organic layer was separated, dried over Na₂SO₄, filtered,and concentrated to give E1 (200 mg, crude) as a solid, which was usedfor next step directly.

Synthesis of Compound 6.

To a solution of E1 (250 mg, 0.43 mmol) in MeOH (30 mL) was added NiCl₂(11 mg, 0.085 mmol) and Mg powder (410 mg, 17 mmol) at 65° C. in oneportion. The mixture was stirred at 65° C. for 10 minutes. Then anotherbatch of Mg powder (200 mg, 8.5 mmol) was added at 65° C. in oneportion. The mixture was stirred at 65° C. for another 10 minutes. Themixture was quenched with HCl (50 mL, 2N) until the reaction becameclear. The mixture was the washed with EtOAc (3×20 mL). The combinedorganic layer was washed with sat. NH₄Cl (50 mL), dried over Na₂SO₄,filtered, concentrated and purified by silica gel chromatography (0-15%of EtOAc in PE) to give impure Compound 6 (40 mg, 21%), which wasfurther purified by SFC ((column: AD (250 mm*30 mm, 10 um), gradient:35-35% B (A=0.05% NH₃/H₂O, B=MeOH), flow rate: 60 mL/min)) to give pureCompound 6 (8 mg, 4%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.31-5.26 (m, 1H), 3.36-3.28 (m, 1H),2.69-2.55 (m, 2H), 2.39-2.31 (m, 1H), 2.25-2.18 (m, 1H), 2.14-1.94 (m,3H), 1.86-1.70 (m, 4H), 1.69-1.58 (m, 4H), 1.47-1.33 (m, 8H), 1.29-1.13(m, 8H), 0.94-0.88 (m, 9H), 0.86-0.82 (m, 3H), 0.65 (s, 3H).

LCMS Rt=1.182 min in 2.0 min chromatography, 30-90AB_E, purity 100%, MSESI calcd. for C₂₉H₄₇O₂ [M+H-H₂O]⁺427, found 427.

Example 6. Synthesis of Compound 7

Synthesis of F1.

To a solution of diisopropylamine (160 mg, 1.60 mmol) in THF (0.5 mL)was added n-BuLi (0.56 mL, 2.5 M in hexane, 1.40 mmol) at −70° C. underN₂. The resulting mixture was stirred at 15° C. for 10 minutes. Asolution of D13 (200 mg, 0.40 mmol) in THF (1.5 mL) was added at −70° C.After stirring at −70° C. for 1 h, (R)-2-isopropyloxirane (52 mg, 0.60mmol) was added at −70° C. The mixture was stirred at −70° C. foranother 1 h, warmed to 15° C. and stirred for 16 hrs. The reactionmixture was quenched with NH₄Cl (50 mL, sat. aq.) and extracted withEtOAc (2×30 mL). The organic layer was separated, dried over Na₂SO₄,filtered, and concentrated to give F1 (200 mg, crude) as a solid, whichwas used for next step without further purification.

Synthesis of Compound 7.

To a solution of F1 (250 mg, 0.43 mmol) in MeOH (30 mL) was added NiCl₂(11 mg, 0.085 mmol) and Mg powder (410 mg, 17 mmol) at 65° C. in oneportion. After stirring at 65° C. for 10 minutes, another batch of Mgpowder (200 mg, 8.5 mmol) was added at 65° C. in one portion and stirredat 65° C. for another 10 minutes. The reaction mixture was quenched withHCl (50 mL, 2N) until the reaction became clear and extracted with EtOAc(3×20 mL). The combined organic layer was washed with saturated NH₄Cl(50 mL), dried over Na₂SO₄, filtered, concentrated and purified bysilica gel chromatography (0-15% of EtOAc in PE) to give impure Compound7 (80 mg, 42%), which was further purified by SFC ((column: AD (250mm*30 mm, 10 um), gradient: 35-35% B (A=0.05% NH3/H2O, B=MeOH), flowrate: 60 ml/min)) to give pure Compound 7 (38 mg, 20%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.32-5.25 (m, 1H), 3.36-3.25 (m, 1H),2.70-2.53 (m, 2H), 2.39-2.31 (m, 1H), 2.25-2.18 (m, 1H), 2.14-1.94 (m,3H), 1.86-1.70 (m, 4H), 1.69-1.56 (m, 5H), 1.53-1.31 (m, 6H), 1.29-1.16(m, 7H), 1.08-0.94 (m, 2H), 0.93-0.88 (m, 9H), 0.87-0.81 (m, 3H), 0.65(s, 3H).

LCMS Rt=1.179 min in 2.0 min chromatography, 30-90AB_E, purity 100%, MSESI calcd. for C₂₉H₄₇O₂ [M+H-H₂O]⁺ 427, found 427.

Example 7. Synthesis of Compound 8

Synthesis of G1.

To a solution of diisopropylamine (320 mg, 3.2 mmol) in THF (0.5 mL) wasadded n-BuLi (1.1 mL, 2.5 M in hexane, 2.8 mmol) at −70° C. under N₂.After addition, the mixture was stirred at 15° C. for 10 minutes. Asolution of D13 (400 mg, 0.80 mmol) in THF (3 mL) was added at −70° C.After stirring at −70° C. for 1 h, 2-(tert-butyl)oxirane (120 mg, 1.2mmol) was added at −70° C. The mixture was stirred at −70° C. foranother 1 h, after which time the mixture was warmed to 15° C. andstirred for 16 hrs. The reaction mixture was quenched with saturatedNH₄Cl (30 mL) and extracted with EtOAc (2×15 mL). The combined organicphase was dried over Na₂SO₄, filtered, and concentrated to give G1 (400mg, crude) as a solid, which was used for the next step directly.

Synthesis of Compound 8.

To a solution of G1 (400 mg, 0.67 mmol) in MeOH (40 mL) was added NiCl₂(17 mg, 0.13 mmol) and Mg powder (640 mg, 27 mmol) at 65° C. in oneportion. After stirring at 65° C. for 10 minutes, another batch of Mgpowder (320 mg, 13 mmol) was added at 65° C. in one portion. Afterstirring at 65° C. for another 10 minutes, the mixture was quenched withHCl (20 mL, 2N) until the reaction became clear and extracted with EtOAc(3×15 mL). The combined organic layer was washed with sat. NH₄Cl (50mL), dried over Na₂SO₄, filtered, concentrated and purified by silicagel chromatography (0-15% of EtOAc in PE) to give impure Compound 8 (80mg, 26%) as a solid.

Example 8. Preparation of Compound 9 and Compound 10

80 mg of Compound 8 was separated by SFC ((column: AD(250 mm*30 mm, 5um), gradient: 35-35% B (A=0.05% NH₃/H₂O, B=MeOH), flow rate: 60mL/min)) to give Compound 9 (Peak 1, 21 mg, 26%) and Compound 10 (Peak2, 13 mg, 16%) as a solid.

SFC of Compound 8

SFC Peak 1: Rt=5.107 min and Peak 2 Rt=6.110 min in 10 minchromatography, AD_3_EtOH_DEA_5_40_25 ML (“Column: Chiralpak AD-3150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5%of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C.”).

Compound 9 Data

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.25 (m, 1H), 3.14-3.04 (m, 1H),2.68-2.54 (m, 2H), 2.38-2.31 (m, 1H), 2.26-2.19 (m, 1H), 2.14-1.93 (m,3H), 1.84-1.69 (m, 5H), 1.68-1.58 (m, 4H), 1.47-1.35 (m, 4H), 1.34-1.23(m, 3H), 1.22 (s, 3H), 1.20-1.14 (m, 1H), 1.11-0.95 (m, 3H), 0.94-0.87(m, 12H), 0.86-0.81 (m, 3H), 0.65 (s, 3H),

LCMS Rt=1.216 min in 2.0 min chromatography, 30-90AB_E, purity 100%, MSESI calcd. for C₃₀H₄₉O₂ [M+H-H₂O]⁺441, found 441.

SFC Rt=5.096 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,100% de.

The absolute stereochemistry of Compound 9 was determined by X-raycrystallography. The structure of Compound 10 was subsequently inferredfrom the X-ray crystal structure of Compound 9.

Compound 10 Data

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.25 (m, 1H), 3.17-3.11 (m, 1H),2.68-2.54 (m, 2H), 2.38-2.31 (m, 1H), 2.26-2.19 (m, 1H), 2.14-1.97 (m,3H), 1.86-1.71 (m, 4H), 1.68-1.58 (m, 3H), 1.50-1.34 (m, 7H), 1.32-1.24(m, 4H), 1.23-1.17 (m, 4H), 1.02-0.94 (m, 1H), 0.93-0.87 (m, 12H),0.86-0.82 (m, 3H), 0.66 (s, 3H).

LCMS Rt=1.211 min in 2.0 min chromatography, 30-90AB_E, purity 100%, MSESI calcd. for C₃₀H₄₉O₂ [M+H-H₂O]⁺441, found 441.

SFC Rt=6.049 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,100% de.

Example 9. Syntheses of Compound 11

Synthesis of H1.

To a solution of B8 (200 mg, 0.5 mmol) in DCM (20 mL) was added DMP (840mg, 2 mmol). After stirring at 15° C. for 2 hrs, the mixture wasfiltered and the filter cake was washed with DCM (2×10 mL). Thefiltrated was quenched with saturated Na₂SO₃ and NaHCO₃ (50 mL, v/v=1/1)and the resulting solution was washed with DCM (2×10 mL) to give H1 (220mg, crude) as an oil, which was used directly.

¹H NMR (400 MHz, CDCl₃) δ 6.91-6.85 (m, 1H), 5.88-5.84 (m, 1H),5.55-5.50 (m, 1H), 5.40-5.39 (m, 1H), 3.75 (s, 3H), 3.35-3.25 (m, 1H),3.02-2.82 (m, 3H), 2.60-1.82 (m, 8H), 1.49-1.15 (m, 8H), 0.90-0.72 (m,5H).

Synthesis of H₂.

To a solution of 2,6-di-tert-butyl-4-methylphenol (610 mg, 2.8 mmol) intoluene (20 mL) was added AlMe₃ (1.40 mL, 2 M in toluene, 2.8 mmol)dropwise at 0° C. After stirring at 15° C. for 1 h, a solution ofcompound H1 (220 mg, 0.55 mmol) in toluene (5 mL) was added dropwise at−78° C. dropwise under N₂. The mixture was stirred at −78° C. for 1 hand MeMgBr (0.92 mL, 3 M in ether, 2.8 mmol) was added dropwise at −70°C. The mixture was stirred at −70° C. for another 1 h, quenched withcitric acid solution (30 mL) and then extracted with EtOAc (2×15 mL).The combined organic phase was dried, filtered, concentrated andpurified by combi-flash (0-25% of EtOAc in PE) to give H₂ (90 mg, 39%)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 6.91-6.85 (m, 1H), 5.84-5.79 (m, 1H),5.51-5.50 (m, 1H), 5.30-5.29 (m, 1H), 3.72 (s, 3H), 2.98-2.92 (m, 1H),2.70-2.62 (m, 1H), 2.49-2.05 (m, 6H), 2.04-1.71 (m, 8H), 1.70-1.11 (m,5H), 1.10-0.91 (m, 1H), 0.90-0.76 (m, 4H), 0.74 (s, 3H).

Synthesis of H3.

To a solution of H2 (90 mg, 0.22 mmol) in THF (10 mL) was added Pd/C(wet, 200 mg). The mixture was stirred at 15° C. for 16 hrs under H2 (15psi). The mixture was filtered and concentrated to give H3 (90 mg, 100%)as an oil.

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.29 (m, 1H), 3.67 (s, 3H), 2.65-2.62 (m,1H), 2.39-2.34 (m, 2H), 2.35-2.24 (m, 2H), 2.22-2.20 (m, 1H), 1.99-1.95(m, 3H), 1.43 (s, 3H), 1.42-1.22 (m, 12H), 1.10 (s, 3H), 0.90-0.89 (m,6H), 0.65 (s, 3H).

Synthesis of Compound 11.

To a solution of H3 (90 mg, 0.22 mmol) in THF (10 mL) was added MeLi(0.68 mL, 1.1 mmol, 1.6 M in THF) under N₂. After stirring at 15° C. for1 h, the mixture was quenched with saturated NH₄Cl (10 mL) and extractedwith EtOAc (3×5 mL). The combined organic phase was dried over Na₂SO₄,filtered, concentrated and purified by flash column (15% of EtOAc inPE/DCM=2/1) to give 35 mg impure product, which was recrystallized fromMeCN (2 mL) for 3 times to give pure Compound 11 (6 mg, 6%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 5.30-5.29 (m, 1H), 2.55-2.45 (m, 1H),2.25-2.15 (m, 1H), 2.10-2.01 (m, 1H), 2.00-1.92 (m, 2H), 1.90-1.71 (m,4H), 1.70-1.58 (m, 2H), 1.55-1.22 (m, 15H), 1.21-0.98 (m, 15H),0.97-0.92 (m, 3H), 0.88 (s, 3H).

LCMS Rt=1.079 min in 2.0 min chromatography, 30-90AB_ELSD, purity 100%,MS ESI calcd. for C₂₈H₄₅O [M+H−2H₂O]⁺397, found 397.

TABLE 1 NMDA Potentiation GluN2A PCA GluN2B PCA IWB Ephys IWB Ephys %potentiation % potentiation Compound at 3 μM at 3 μM Compound 1 B BCompound 2 A A Compound 3 A B Compound 4 B B Compound 11 B B

For Table 1, “A” indicates % potentiation up to 100%, and “B” indicatespotentiation of >100% as described in the above section entitled“Potentiating effect of positive allosteric modulators (PAM) on thechannel.”

TABLE 2 EC₅₀ and E_(Max) Data GluN2A GluN2B GluN2A GluN2B PCA PCA PCAPCA Compound EC₅₀ (nM) EC₅₀ (nM) E_(Max) (%) E_(Max) (%) Compound 1 E EI I Compound 2 F E H H Compound 3 G E H I Compound 4 D D I I Compound 5D D I I Compound 6 C C I I Compound 7 C C I I Compound 9 C C J ICompound 10 C C J I Compound 11 E F I I

For Table 2, “C” indicates an EC₅₀ of 1 to 100 nM, “D” indicates an EC₅₀of greater than 100 nM up to 500 nM, “E” indicates an EC₅₀ greater than500 nM up to 1 μM; “F” indicates an EC₅₀ of greater than 1 μM to 9.999μM; “G” indicates an EC₅₀ greater than or equal to 10 μM, “H” indicatesan E_(Max) of up to 100%, and “I” indicates an E_(max), between 100% and500%, and “J” indicates an E_(max) greater than 500%.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogenor C₁-C₆ alkyl; each of R² and R³ is independently hydrogen, C₁-C₆alkyl, or carbocyclyl, or R² and R³, together with the carbon atom towhich they are attached, form a 3-8 membered ring; R⁶ is absent orhydrogen; R^(11a) is hydrogen or C₁-C₆ alkyl and R^(11b) is OH or C₁-C₆alkyl, or R^(11a) and R^(11b) are joined together to form oxo; and

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond; and when one of the

is a double bond, R⁶ is absent.
 2. The compound of claim 1, wherein R¹is C₁-C₆ alkyl.
 3. The compound of claim 1, wherein R¹ is hydrogen,methyl, ethyl, —CHF₂, —CF₃, —CH₂OCH₃, or —CH₂OCH₂CH₃.
 4. The compound ofclaim 1, wherein R¹ is unsubstituted C₁-C₆ alkyl.
 5. The compound ofclaim 1 wherein R¹ is hydrogen.
 6. The compound of claim 1, wherein R¹is —CH₃.
 7. The compound of claim 1, wherein R¹ is —CH₂CH₃.
 8. Thecompound of claim 1, wherein each of R² and R³ is independentlyhydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, —CF₃, or—CH₂CF₃.
 9. The compound of claim 8, wherein each of R² and R³ isindependently methyl, isopropyl, or tert-butyl.
 10. The compound ofclaim 8, wherein R² is hydrogen, methyl, ethyl, or —CF₃.
 11. Thecompound of claim 1, wherein R³ is methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, —CF₃, or —CH₂CF₃.
 12. The compound of claim 1,wherein R^(11a) is hydrogen and R^(11b) is —OH.
 13. The compound ofclaim 1, wherein R^(11a) is C₁-C₆ alkyl and R^(11b) is —OH.
 14. Thecompound of claim 1, wherein R^(11a) and R^(11b) are joined together toform oxo.
 15. The compound of claim 1, wherein the compound of Formula(I) is a compound of Formula (I-A) or Formula (I-B):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein the compound of Formula (I) is a compound of Formula (II-A)or Formula (II-B):

or a pharmaceutically acceptable salt thereof.
 17. A compound selectedfrom the group consisting of:


18. A pharmaceutically acceptable salt of a compound selected from thegroup consisting of:


19. The compound of claim 1, wherein the compound of Formula (I) is acompound of Formula (III):

or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a compound of claim 1, or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.